This invention relates to methods of treating patients afflicted with mast cell mediated diseases, including urticaria, atopic dermatitis, psoriasis, pruritus, asthma, rhinitis, mastocytosis, conjunctivitis and keratoconjunctivitis.
Mast cells (MC) and blood basophils are crucial components of the acquired and innate human immune system. The different subtypes are found in almost all tissues, most abundantly in the skin and the respiratory and gastrointestinal tract. Mast cells are the primary effector cells in immunoglobulin E (IgE) mediated inflammatory reactions and are involved in maintenance of skin and mucosal homeostasis as well as in neurohumoral interactions associated with various inflammatory processes, such as allergic inflammation. Mast cells are involved in certain inflammatory dermatologic diseases, such as urticaria, cutaneous mastocytosis, atopic dermatitis and psoriasis and in the polyetiological pruritus. Mast cells are also involved in extracutaneous diseases such as rhinitis, systemic mastocytosis, allergic and non-allergic asthma bronchiale, conjunctivitis and keratoconjunctivitis. A key event in mast cell triggered inflammatory processes is mast cell degranulation, in which an extensive mixture of different cytokines and neurotransmitters (such as serotonin and/or histamine) is delivered to surrounding tissue.
Mast cells differentiate from bone-marrow derived CD34+ myeloic precursor cells. After leaving the blood stream, these precursors differentiate under the influence of local growth factors to mature tissue mast cells (Wedemeyer et al. 2000, Curr Opin Immunol. 2000; 12(6):624-31). Mast cells reside in close proximity to vessels, nerves and surface epithelium. In human skin, the highest density of mast cells can be found around hair follicles, sweat glands, sebaceous glands and capillaries of the stratum papillare (Toruniowa, Jablonska 1988). Anatomical and functional interactions between mast cells and peripheral nerves have also been reported (Bienenstock et al. 1987 Int Arch Allergy Appl Immunol 82: 238-43; Naukkarinen et al. 1996. J Pathol. 1996; 180(2):200-5).
Mast cells have a diameter of 9-11 μm and are characterized by numerous basophilic granules. Mast cells are important effectors of allergic reactions. Mast cells play an important role in many physiological and pathological processes because of their susceptibility to numerous activating stimuli and their ability to release a plethora of different mediators. Mast cells have been implicated in numerous skin and mucosal diseases, including inflammation, hypersensitivity, and tissue repair (Benoist and Mathis, 2002; Nature. 2002; 420(6917):875-8). Mast cells communicate with sensory nerves and blood vessels via histamine release, thereby regulating neurogenic inflammation and pruritus (Steinhoff et al., 2003, Arch Dermatol. 2003; 139(11):1479-88.
Urticaria is a dermatological disease which involves activated mast cells. In urticarial lesions, mast cells are degranulated, and the effects of vasoactive mast cell components like histamine dominate the clinical symptoms. Many patients suffer from hives, pruritus and soft tissue swelling. The causes of urticaria are numerous, indeed, there are different entities ranging from acute urticaria as symptom of an allergic anaphylaxis, e.g. after ingestion of peanuts in a peanut allergic patient. Type I allergies are unique in this context because a specific mechanism and a specific agent are necessary to induce this effect. In other forms of urticaria, either specific triggers are unknown or do not exist (Maurer, et al., Hautarzt. 2003; 54(2):138-43). Urticaria may also occur in association with a viral or bacterial infection. Neuroendocrine factors are also known to be involved in the onset of e.g. adrenergic or cholinergic urticaria, both of which occur after physical exercise (Maurer et al., Hautarzt. 2004; 55(4):350-6; Mlynek et al., Curr Opin Allergy Clin Immunol. 2008; 8(5):433-7).
Typical treatment of urticaria involves blockage of histamine receptors of the H1 and, less commonly, the H2 subtype. Other pharmacological agents (such as cromoclycine acid or montelukast) have been reported to “stabilize” mast cell membranes; however, these agents have also been reported as less effective in the treatment of urticaria. Moreover, in severe cases, steroids need to be administered to prevent the onset of anaphylaxis.
One of the main drawbacks associated with current treatments for urticaria is the low efficacy of antihistamines in severe, life-threatening forms of acute urticaria and in the treatment of chronic forms of urticaria that do not have a determinable cause and are therefore referred to as idiopathic. Some patients suffer from idiopathic forms of urticaria for several years and have a strongly reduced quality of life (Mlynek et al., Curr Opin Allergy Clin Immunol. 2008; 8(5):433-7).
Psoriasis is a polygenetic hereditary multifactorial inflammatory skin disease of complex pathogenesis, which may be influenced by a number of environmental factors. Despite substantial progress regarding the pathogenetic mechanisms involved in this disease, many factors still remain unresolved. Mast cells and macrophages are prominent in intial and developing psoriatic lesions, but are also found in stable lesions. Although late events leading to the clinical psoriatic phenotype are well understood (e.g., involvement of Th1 dominated cytokines leading to the epidermal psoriatic reaction pattern), early events which might unravel genetic alterations and crucial pathogenetic checkpoints remain obscure.
Several lines of evidence suggest an involvement of the cholinergic system in the pathogenesis of psoriasis. More than 50 years ago a Hungarian study group treated psoriasis patients with the anticholinergic substance atropine, based on the assumption that the parasympathetic nervous system must be responsible for an increased content of acetylcholine in the psoriatic lesions thus initiating the onset and mediating the course of the disease (Helmeczi, Dermatologica, 1955 110: 439-48). A careful analysis of the patients presented in Helmeczi's study reveals that almost exclusively those patients with “eruptive psoriasis” responded to the oral atropine treatment, while those with chronic plaque type psoriasis generally did not. According to several histological studies, the first cells that “arrive” in psoriasis lesions are mast cells and neutrophilic granulocytes. Indeed mast cells have been found significantly increased in number especially in guttate psoriasis and palmoplantar psoriasis (Schubert and Christophers, Arch Dermatol Res 1985; 277:352-8; Brody, J Invest Dermatol. 1984 May; 82(5):460-4; Naukkarinen et al., J Pathol. 1996 October; 180(2):200-5; Ashenagar et al., Arch Dermatol Res. 2007 February; 298(9):421-6) while chronic lesions are dominated by lymphocytes and macrophages (Ghoreschi K and Röcken M; J Dtsch Dermatol Ges 2003; 1: 524-32).
One study demonstrates a significant increase of mast cells in chronic psoriasis lesions only in patients complaining of pruritus (Nakamura et al. 2003 Br J Dermatol;149(4):718-30), while other immune cells and cytokines did not show any difference. In addition, mast cell degranulation has been shown to induce ICAM-1 expression in psoriatic epidermis, thus initiating the inflammatory cascade (Ackermann and Harvima, Arch Dermatol Res. 1998 July; 290(7):353-9). There is additional evidence for a role of mast cells in psoriasis from a mouse model. The so called flaky mouse (congenic fsn/fsn) shows diffuse epidermal orthokeratotic hyperkeratosis reminding strongly of psoriasis. In this mouse, numerous mast cells are lining up under the epidermis (Sundberg et al., Eur J Immunol 1998 April; 28(4):1379-88). The close “synapse-like” proximity of mast cells with free nerve endings containing a plethora of proinflammatory neurotransmitters together with their well-documented responsiveness to “stress-hormones” like CRH and urocortin, makes mast cells the ideal target for stress related and neurogenic inflammatory processes (Arck et al., J Mol. Med. 2005; 83(5):386-96) which fits well to the clinical association of psoriasis with emotional stress (Singh et al., J Pharmacol Exp Ther. 1999 March; 288(3):1349-56). The physiological function of mast cells has been discussed intensely (Maurer et al., Exp Dermatol. 2003 December; 12(6):886-910); however, it has been convincingly demonstrated that mast cells are key cells of neuroendocrine inflammatory processes (Arck et al., J Mol. Med. 2005; 83(5):386-96; Siebenhaar, et al., J Allergy Clin Immunol. 2008; 121(4):955-61) that can be stimulated by a great variety of different stimuli, amongst them, acetylcholine (Fantozzi et al. 1978 Nature 273: 473-4).
There are several psoriasis treatment protocols aiming at secretory products of mast cells, in particular histamine. The use of H1-R and H2-R blockers has been suggested and documented in small studies (Kristensen et al., Br J. Dermatol. 1995 December; 133(6):905-8; Petersen et al., Acta Derm Venereol. 1998 May; 78(3):190-3); however, randomized controlled trials did not show significant therapeutic effects. These results/lack of effect may have been due to using the PASI score and not the psoriasis subtype or acuity as stratification factor (Zonneveld et al., J Am Acad Dermatol. 1997 June; 36(6 Pt 1):932-4. 7-103).
Several changes in the cholinergic system have been documented in psoriatic lesions: SLURP-2 is a peptide modulator of nicotinic cholinergic receptors that has been found elevated in psoriatic lesions. SLURP-2 has been shown to inhibit caspase-3 and filaggrin and, therefore, has been suggested to be involved in psoriasis through its role in keratinocyte hyperproliferation and/or T cell differentiation/activation (Tsuji et al., Genomics 2003; 81(1):26-33).
Smoking increases the risk of psoriasis at least in a subset of patients. This effect most probably is related to the main cigarette toxin, nicotine, a ligand of the nicotinic acetylcholine receptor (nAChR) (Arathi et al., Am J Med, 2007, 120 (11): 953-959) also active at the α10 nAChR present in mast cells. In addition, a special form of psoriasis, the pustulosis palmoplantaris (PPP) correlates strongly with smoking PPP lesions are particularly rich in mast cells expressing acetylcholine esterase (AChE) and granulocytes expressing ChAT and α3 nAChR. (Hagforsen et al., Acta Derm Venereol 2002; 82(5):341-6).
Mast cells are also key effector cells in bronchial asthma. Anticholinergic substances acting on the muscarinic acetylcholine receptor (mAChR) are on the market (tiotropium) for the treatment of asthma. It has been suggested that there may be an involvement of both neuronal and non-neuronal derived ACh in lung mucosal inflammation, involving lymphocytes and macrophages, mast cells (Wessler and Kirkpatrick, Pulm Pharmacol Ther. 2001; 14(6):423-34). This notion has immediate impact on the issue of tobacco-derived nicotine action in lung diseases on the one hand, and the use of anti-muscarinic drugs in chronic airway diseases on the other hand.
Rhinitis involves inflammation and swelling of the mucous membrane of the nose, characterized by a runny nose and stuffiness, and is usually caused by the common cold or an allergy.
Allergic rhinitis is the most common cause of rhinitis. It is an extremely common condition, affecting approximately 20% of the population. While allergic rhinitis is not a life-threatening condition, complications can occur and the condition can significantly impair quality of life, which leads to a number of indirect costs. The total direct and indirect cost of allergic rhinitis was recently estimated to be $5.3 billion per year.
Allergic rhinitis involves inflammation of the mucous membranes of the nose, eyes, eustachian tubes, middle ear, sinuses, and pharynx. The nose invariably is involved, and other organs are affected in certain individuals. Inflammation of the mucous membranes is characterized by a complex interaction of inflammatory mediators but ultimately is triggered by an immunoglobulin E (IgE)-mediated response to an extrinsic protein.
The tendency to develop allergic, or IgE-mediated, reactions to extrinsic allergens (proteins capable of causing an allergic reaction) has a genetic component. In susceptible individuals, exposure to certain foreign proteins leads to allergic sensitization, which is characterized by the production of specific IgE directed against these proteins. This specific IgE coats the surface of mast cells, which are present in the nasal mucosa. When the specific protein (e.g., a specific pollen grain) is inhaled into the nose, it can bind to the IgE on the mast cells, leading to immediate and delayed release of a number of mediators.
The mediators that are immediately released include histamine, tryptase, chymase, kinins, and heparin. The mast cells quickly synthesize other mediators, including leukotrienes and prostaglandin D2. These mediators, via various interactions, ultimately lead to the symptoms of rhinorrhea (ie, nasal congestion, sneezing, itching, redness, tearing, swelling, ear pressure, postnasal drip). Mucous glands are stimulated, leading to increased secretions. Vascular permeability is increased, leading to plasma exudation. Vasodilation occurs, leading to congestion and pressure. Sensory nerves are stimulated, leading to sneezing and itching. All of these events can occur in minutes; hence, this reaction is called the early, or immediate, phase of the reaction.
Over 4-8 hours, the above-mentioned mediators, through a complex interplay of events, lead to the recruitment of other inflammatory cells to the mucosa, such as neutrophils, eosinophils, lymphocytes, and macrophages. This results in continued inflammation, termed the late-phase response. The symptoms of the late-phase response are similar to those of the early phase, but less sneezing and itching and more congestion and mucus production tend to occur. The late phase may persist for hours or days.
Atopic dermatitis is a pruritic disease of unknown origin that usually starts in early infancy (an adult-onset variant is recognized); it is characterized by pruritus, eczematous lesions, xerosis (dry skin), and lichenification (thickening of the skin and an increase in skin markings). Atopic dermatitis may be associated with other atopic (immunoglobulin E [IgE]) diseases (e.g., asthma, allergic rhinitis, urticaria, acute allergic reactions to foods). Atopic dermatitis has enormous morbidity, and the incidence and prevalence appear to be increasing.
Substantial evidence indicates that genetic factors are important in the development of atopic dermatitis (AD), but the pathophysiology is still poorly understood. Two main hypotheses have been proposed regarding the development of the inflammatory lesions. The first suggests an immune dysfunction resulting in IgE sensitization and a secondary epithelial-barrier disturbance. The second proposes a defect in epithelial cells leading to the defective barrier problem, with the immunological aspects being epiphenomena.
Pruritus is a common manifestation of dermatologic diseases, such as urticaria, atopic dermatitis, and other allergic reactions. Effective treatment of pruritus can prevent scratch-induced complications such as lichen simplex chronicus and impetigo.
Pruritus originates within the skin's free nerve endings, which are most heavily concentrated in the wrists and ankles. The sensation of pruritus is transmitted through C fibers to the dorsal horn of the spinal cord and then to the cerebral cortex via the spinothalamic tract. Pruritus generates a spinal reflex response, the scratch, which is as innate as a deep tendon reflex. Regardless of the cause, pruritus often is exacerbated by skin inflammation, dry or hot ambient conditions, skin vasodilation, and psychologic stressors.
Histamine, which is released by mast cells in persons with urticaria and other allergic reactions, is one of the factors classically associated with pruritus.
As noted above, there are various disadvantages associated with the available treatments for mast cell mediated diseases such as urticaria, atopic dermatitis, psoriasis, pruritus, asthma, rhinitis, mastocytosis, conjunctivitis and keratoconjunctivitis. Thus, a need exists for improved treatments for urticaria, atopic dermatitis, psoriasis, pruritus, asthma, rhinitis, mastocytosis, conjunctivitis and keratoconjunctivitis and other mast cell mediated diseases.
1-Amino-alkylcyclohexane derivatives such as neramexane (also known as 1-amino-1,3,3,5,5-pentamethylcyclohexane) have been found to be useful in the therapy of various diseases especially in certain neurological diseases, including Alzheimer's disease and neuropathic pain. 1-Amino-alkylcyclohexane derivatives such as neramexane are disclosed in detail in U.S. Pat. Nos. 6,034,134 and 6,071,966, the subject matter of which patents is hereby incorporated by reference. It is believed that the therapeutic action of 1-amino-alkylcyclohexanes such as neramexane is related to the inhibition of the effects of excessive glutamate at the N-methyl-D-aspartate (NMDA) receptors of nerve cells, for which reason the compounds are also categorized as NMDA antagonists, or NMDA receptor antagonists.
Neramexane is also a blocker of the α9α10 nicotinic Acetylcholine Receptor. Neramexane behaves as a non-competitive antagonist. Since blockage by neramexane at concentrations higher than 1 mM has been reported to be only slightly dependent on the membrane potential and has also been reported not to modify the rate of desensitization, an additional mechanism might be involved. (Plazas, Paola V. et al., European Journal of Pharmacology 2007; 566: 11-19).